Hippocampal Adaptive Response Following Extensive Neuronal Loss in an Inducible Transgenic Mouse Model

Abstract

Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease) and brain traumas (stroke, epilepsy, and traumatic brain injury). One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DTA mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.

Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease

“…Further, the CaM/Tet-DT A mice which are characterized by a selective neuronal loss in the hippocampus, have increased neurogenesis and angiogenesis, correlating with behavioural recovery, suggestive of a compensatory response (56). Despite increased neurogenesis in this mouse model, cognitive deficits were ameliorated only in the young (6-month old) (56) but not old (14-month old) mice (57).…”

Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology

“…Cresyl violet staining was performed on fixed tissue and neurons in the subiculum were counted in a double-blind unbiased stereological fashion, as previously described (Myczek et al, 2014). All unbiased stereological assessments were performed using Stereo Investigator (MBF Bioscience) and Neurolucida softwares.…”

Predicting progression to Alzheimer’s disease with human hippocampal progenitors exposed to serum

“…It is not clear whether increased HN plays a compensatory role by providing cognitive resilience or contributes to ongoing pathology in Alzheimer’s disease. For example, increased neurogenesis was associated with behavioural recovery in a mouse model of selective neuronal loss in the hippocampus (CaM/Tet-DTA), although this effect was only pronounced in young mice (6 months old) 53 and not in old mice (14 months old). 54 This suggests that increased HN at the later stages of Alzheimer’s disease might be insufficient for cognitive recovery.…”